Abstract This proposal outlines a 5-year career development plan for Ryan M. O'Connell, Ph.D., that begins with a 2 year mentored period and finishes with 3 years of independent research upon obtaining a tenure track position at an academic institution. The principal investigator (P.I.) has undergone 3 previous years of training as a postdoctoral scholar in the laboratory of David Baltimore, Ph.D., at the California Institute of Technology where significant research progress has been made in the field of miRNAs and the immune system. During the mentored phase of the proposed project, the P.I. will continue to work in Dr. Baltimore's laboratory and receive additional guidance in specific areas important for carrying out the proposed research agenda. The proposed work will next be completed during the independent period. The overall scientific goal of this proposal is to understand how mammalian hematopoiesis is regulated by microRNAs during inflammatory stress. This research direction is supported by compelling preliminary data, and the overwhelming medical need to understand how hematopoietic stress contributes to diseases such as cancer, anemia, immunodeficiency, and autoimmunity. The P.I. has previously identified a specific microRNA, miR-155, that is induced in the hematopoietic system during inflammation and sufficient to cause a myeloproliferative disorder upon its sustained expression in the hematopoietic system. Therefore, the central hypothesis to be tested is whether physiologically regulated miR-155 promotes myeloid expansion during inflammation, and does so by directly repressing SHIP1 and selecting specific C/EBP protein isoforms to be expressed. Results will determine whether miRNAs regulate hematopoiesis during physiologically relevant inflammatory stress, and provide a mechanistic basis for this function. Furthermore, important insights will be gained regarding how miRNAs can serve as links between inflammation and hematological disorders.